Neurotoxicity Of General Anesthetics Research Articles

Effects of general anesthetics on the cognitive function of pediatric patients: A review

The consequences induced by the use of general anesthetics and better options of the drugs in children and infants have been topics of controversy due to the concerns about their potential impact on cognitive function. To address these concerns and ensure the safety of pediatric general anesthesia, this paper reviews existing basic and clinical studies that have investigated the mechanisms of general anesthetics on pediatric cognitive function. In this paper, the basic research on neurotoxicity of general anesthetics and the clinical research on the effects of general anesthesia drugs on cognitive function in children in recent years were analyzed and summarized. Although some of the clinical studies have suggested that general anesthesia in children or infants may cause neurocognitive damage and a series of behavioral complications, the results of the retrospective studies need to be viewed with caution as they may lack effective control for relevant factors that could have impacts in the perioperative period. It remains uncertain whether general anesthetics affect the cognitive function of pediatric patients. Further research is needed to establish clear evidence-based recommendations for clinical prevention and treatment measures to minimize the potential risks associated with the use of general anesthetics.

ATPase Inhibitory Factor 1 Is Critical for Regulating Sevoflurane-Induced Microglial Inflammatory Responses and Caspase-3 Activation.

Postoperative delirium (POD) is one of the most important complications after surgery with general anesthesia, for which the neurotoxicity of general anesthetics is a high-risk factor. However, the mechanism remains largely unknown, which also hinders the effective treatment of POD. Here, we confirmed that a clinical concentration of the general anesthetic sevoflurane increased the expression of inflammatory factors and activated the caspase-3 by upregulating ATPase inhibitory factor 1 (ATPIF1) expression in microglia. Upregulation of ATPIF1 decreased the synthesis of ATP which is an important signaling molecule secreted by microglia. Extracellular supplementation with ATP attenuated the microglial inflammatory response and caspase-3 activation caused by sevoflurane or overexpression of ATPIF1. Additionally, the microglial inflammatory response further upregulated ATPIF1 expression, resulting in a positive feedback loop. Animal experiments further indicated that intraperitoneal injection of ATP significantly alleviated sevoflurane anesthesia-induced POD-related anxiety behavior and memory damage in mice. This study reveals that ATPIF1, an important protein regulating ATP synthesis, mediates sevoflurane-induced neurotoxicity in microglia. ATP supplementation may be a potential clinical treatment to alleviate sevoflurane-induced POD.

The effect of sevoflurane anesthesia for dental procedure on neurocognition in children: a prospective, equivalence, controlled trial

BackgroundDental procedures under general anesthesia (DGA) was found to improve the oral health-related quality of children’s life. However, some parents and pediatricians expressed concern about the neurotoxicity of general anesthesia. The purpose of this trial was to whether DGA in children has an adverse effect on neurocognition.MethodsIn this prospective, assessor-masked, controlled, equivalence trial, we recruited 340 children younger than 7 years who were undergoing caries treatment between Feb 1, 2019, and Aug 31, 2019, without factors affecting neurodevelopment. They received either sevoflurane-based general anesthesia or awake-local anesthesia. The Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition was used to evaluate the neurocognitive function of children at 6 months after surgery, and the Full-Scale IQ (FSIQ) was selected as the primary outcome. The predefined clinical equivalence margin was 5 (1/3 SD of FSIQ score). If the 95% CI of the difference between the average FSIQ score of the two groups is within − 5 to + 5, then the two groups are equivalent.ResultsThe outcome data were obtained from 129 children in the general anesthesia group and 144 in the local anesthesia group. The median length of general anesthesia was 130 min (IQR 110–160). The mean FSIQ score in the general anesthesia group was 103·12 (SD 8.94), and the mean of the local anesthesia group was 103·58 (SD 8.40). There was equivalence in means of FSIQ score between the two groups (local minus general anesthesia 0.46, 95% CI − 2.35 to 1.61). There was no significant difference in FSIQ scores between different age groups and different anesthesia durations. Only the mother’s education could affect the primary outcome.ConclusionsIn this trial, prolonged DGA with a sevoflurane-only anesthetic in preschool children, does not adversely affect neurocognitive function at 6 months after surgery compared with awake-local anesthesia.Trial registrationChinese Clinical Trial Registry, ChiCTR1800015216. Registered Mar 15 2018.

Neurodevelopmental Effect of General Anesthesia on the Pediatric Patient.

In this article, the authors review the animal and human data on the recent studies looking at the neurotoxicity of general anesthesia in the pediatric population. Animal studies in rodents and non-human primates demonstrate neurotoxic effects when exposed to general anesthesia at a young age. However, prospective clinical studies in humans do not show significant differences in intelligence quotient outcomes in children younger than 3 years with isolated and/or short exposures. Current studies are investigating alternatives to minimize the potential side effects, including the addition of protective agents to the anesthetic mix. Understanding the findings regarding the laboratory and clinical studies on the effects of general anesthesia is important in guiding both patient care and parent education. This is particularly relevant in the care of children with ophthalmic conditions such as trauma, congenital cataract, and congenital glaucoma, which may require urgent surgery and early anesthetic exposure. [J Pediatr Ophthalmol Strabismus. 2019;56(6):349-353.].

Neurotoxicity of general anesthetics in children: evidence and uncertainties.

Compelling evidence in animal models that, under some conditions, general anesthetics and sedatives produce changes in the brain and persistent impairments in learning, memory, and behavior. The present review summarizes recent clinical studies investigating whether the use of these agents in children causes similar neurotoxicities. Although the results of retrospective studies are somewhat mixed, multiple exposures to general anesthesia were generally found to confer greater risk than single exposures with regard to learning disability, attention deficit hyperactivity disorder, school readiness, and academic achievement. Recent clinical studies, including a large randomized controlled trial, are consistent in confirming that a single exposure in infancy to general anesthesia lasting less than 1 h is not associated with neurodevelopmental impairments in later childhood. These studies do not, however, clarify the potential impacts of longer exposures or multiple exposures. Given that approximately half of the anesthetic exposures in young US children are 1 h or less in duration, the results of the recent clinical studies are reassuring. Because of the clinical necessity of administering general anesthetics and sedatives for longer periods for many surgical, procedural, or diagnostic purposes, the identification of adjuvants that prevent or reduce the potential neurotoxicity of these agents is an area of active research.

Basic studies on neurotoxicity of general anesthetics in the developing brain

Animal researches on the toxicity of general anesthetics, mainly include laboratory studies from the rodent and non-human primate species. Basic studies have confirmed that general anesthetics can cause widely apoptosis in vulnerable regions of brain, changes on neurogenesis, synaptic plasticity, development of glial cells, and a series of histopathological changes. However, it is still uncertain of the relationship between the histopathological changes and cognitive changes, as well as learning and memory. And basic studies have also confirmed that the outcome of cognition and learning memory disfunction is related to the species of anesthetics, the exposure period, the exposure frequency and other factors. To make a review of recent animal researches on the neurotoxicity of the general anesthetic in fields of histopathology and long-term behavior in the developing period, to further explore the neurotoxic effect of general anesthetics on the development of brain in the development of the brain through animal experiments, and provide a theoretical basis for clinical research. Key words: Anesthetics, general; Developing period; Neurotoxicity; Basic research

Sevoflurane-induced learning deficits and spine loss via nectin-1/corticotrophin-releasing hormone receptor type 1 signaling

In recent years, the neurotoxicity of general anesthetics in the developing brain has been studied and raised great concern as a major health issue to the public and physicians. Sevoflurane inhalation may induce neurotoxicity expressed as memory and learning impairment in young animals. In the current study, we investigated the role of nectin-1 and corticotrophin-releasing hormone receptor type 1 (CRHR1) in sevoflurane-induced learning deficits and dendritic spines loss in neonatal mice. Neonatal mice (P7) were treated with 3% sevoflurane with 60% O2 or 60% O2 for 6 h. Cognitive function was evaluated by Y Maze, Object recognition test, and Morris Water Maze. Hippocampal nectin-1 and L-afadin expression assessed using western blot analysis. The dendritic spines morphology of the hippocampus was determined using Golgi impregnation on 7 d and 2 months old. Sevoflurane exposed to neonatal mice decreased hippocampal nectin-1 levels from 1 h to 2 months after sevoflurane inhalation and attenuated working and spatial memory and spinal number in adulthood, which could be reversed by nectin-1 overexpression and CRHR1 antagonist Antalarmin. Nectin-1 knockdown caused spatial learning deficits and dendritic spine loss and lower L-afadin protein expression. Sevoflurane-induced nectin-1 and L-afadin expression decrease was mediated by CRHR1 signaling in the hippocampus. This information can be used to develop targeted intervention aimed at decreasing the neurotoxicity of sevoflurane inhalation.

Common challenges and coping strategies in pediatric anesthesia

Background Progress in pediatrics, anesthesiology, apparatus for anesthesia, and computerized technology promotes the development of pediatric anesthesia. But pediatric anesthesia currently lags far behind adult anesthesia as the incidence of postoperative complications and mortality rate in pediatric patients is still higher than those in adult patients. Objective To review the recent advancement in pediatric anesthesiology and provide guidance for the practice of pediatric anesthesia. Content Recent radiological imaging and bronchoscopy studiesreveal the location and shape of the narrowest part of children's trachea. This finding provides anatomical guidance for appropriate performance of balloon catheter intubation.The treatment of obtrusive sleep apnea(OSA) in pediatric patients requires tonsillectomy. In these cases, dexamethasone, serotonin receptor blockers and metoclopramide can alleviate postoperative complications. Airway management is more challenging in pediatric anesthesia than in adult anesthesia and requires tranquilizer treatment and real-time monitoring to avoid adverse reactions. Appropriate perioperative anesthesia and analgesia management may effectively control emergence agitation. Neurotoxicity of general anesthetics is another important concern for pediatric anesthesia. Trend Further clinical investigations are required to optimize intervention strategies to prevention adverse outcomes in pediatric anesthesia and to clarify the cause-effect relationship between anesthesia and neurodevelopmental deficits. Key words: Pediatric; Anesthesia; Airway management; Obstructive sleep apnea hyponea; Emergence igitation; Neurotoxicity

Recent advances on neurotoxicity of general anesthetics

Background Results of in vivo and in vitro animal studies have raised a significant concern that commonly used general anesthetics may induce neurotoxicity in the developing brain. Objective To make a review of the recent advances in pre-clinical studies that focused on the potential neurotoxicity of general anesthetics. Content Effects of anesthetics on apoptotic neuronal death, synapse formation and function, dendrite elaboration and axon guidance, and neurogenesis were identified as possible mechanisms of anesthetic-induced toxicity in the immature brain, which may cause long-term neurobehavioral deficits. Trend Making further improvement on understanding of general anesthetic induced neurotoxicity may provide potential therapeutic targets for the long-term cognitive deficits. Key words: Anesthetics, general; Immature brain; Neurotoxicity

Developmental neurotoxicity of general anesthesia: underlying mechanisms, prevention, and treatment

Background More and more animal studies have demonstrated that general anesthesia can cause apoptosis in developing neurons. Epidemiological studies also demonstrate that long time or repetitive general anesthesia significantly increases the risk of postoperative cognitive dysfunction in young children less than 3 years old. However, the mechanisms of general anesthesia-induced developmental neurotoxicity is still unclear, meanwhile, no effective strategy for prevention and treatment has been found. Objective To explore the potential strategies for prevention and treatment by reviewing the mechanisms underlying developmental neurotoxicity of general anesthetics. Content General anesthetics modulate a variety of molecules in developing neurons and initiate or exacerbate apoptosis. First, as developing neurons contain high concentrations of Cl-, enhancement of γ-aminobutyric acid (GABA) A receptors by general anesthetics strengthens efflux of Cl- upon GABA stimulation, and subsequently leads to excitotoxicity of neurons. Second, upregulation of calcium-permeable N-methyl-D-aspanate(NMDA) receptors by ketamine may result in calcium overload. Third, general anesthetics inhibit the transformation of brain derived neurotrophic factor(BDNF) from prototype to mature one, which may induce apoptosis through p75 neurotrophin receptor(P75NTR) pathway. Fourth, some general anesthetics also cause accumulation of reactive oxygen species(ROS). Together with calcium overload, ROS induces mitochondrial malfunction. The neuronal apoptosis after general anesthesia can be followed by dysfunction of neural network and confer cognitive deficits. Accumulating studies found that targeting related ion channels, controlling calcium overload, reducing ROS production, and attenuating apoptosis can effectively protect neurons from degeneration following general anesthesia. Trend General anesthesia can cause apoptosis in developing neurons by targeting a variety of molecules, and these molecules or processes involving these molecules can be potential targets to prevent and treat general anesthesia-induced malfunctions. Key words: Neurotoxicity; Anesthesia general; Development; Apoptosis; Prevention and treatment

Research advances on neurotoxicity to developing brain of general anesthetics

Background General anesthetics and sedatives are repeatedly used, worldwide, in millions of neonates and infants every year for a variety of surgical operations, and in emergency departments and intensive care units, so people have noticed whether prolonged neonatal exposure to numerous anesthetics may cause widespread neurotoxicity. Objective To discuss the research advances on neurotoxicity and potential mechanisms of general anesthetics to developing brain. Content This article respectively describes the potential neurotoxicity mechanisms of general anesthetics, and advances on different studies of animal and clinical research and their relevance and limitations. Trend Currently animal and clinical studies cannot be completely ruled out neurotoxicity of general anesthetics. Emphasize the mechanism of the developing nervous system deeply while minimize neurotoxic side effects of pediatric general anesthesia. Key words: Anesthetics, general; Infants; Neurotoxicity

Neurotoxicity of general anesthetics: A modern view of the problem

All general anesthetics routinely used in clinical practice are noted to have a neurotoxic effect on the brain in different animal species including primates. The negative effects observed both in young and sexually mature animals include apoptotic neuronal cell death, suppression of neurogenesis and gliogenesis, neuroinflammation, as well as learning and memory impairments. A number of epidemiologic surveys have established an association between anesthesia in patients younger than 3 to 4 years and subsequent learning disabilities and language disorders whereas others have not found this link. In middle-aged and elderly patients, anesthesia is frequently associated with the development of postoperative cognitive dysfunction. The key component of its pathogenesis (general anesthesia itself or other factors, such as operative injury, an inflammatory response, pain syndrome, intraoperative complications, underlying disease in a patient) remains unelucidated. It is concluded that there is a need for additional experimental and clinical studies of the pathogenesis of these undesirable phenomena to be prevented and corrected.

Research progress on neurotoxicity of general anesthetics in the developing brain

Background A great deal of laboratory work has confirmed that general anesthetics kill neurons in the developing brains of animals,and cause permanent and progressive neurocognitive dysfunction.And claims high attention to the safety of anesthesia in human neonates and infants.Objective This review gives an overview of the mechanisms of anesthesiainduced cognitive dysfunction,possible prevention/treatment options,early results of comparative animal studies of anesthetic neurotoxicity,and discusses of the recent clinical evidence.Content The animal studies have disputed evidence for three cellular phenomena to qualify as a mediating mechanism of anesthesia-induced cognitive dysfunction:neuroapoptosis,synaptic plasticiy and hippocampal neurogenesis.Based on them,the animal models have addressed the early issues in possible prevention/treatment options and comparative anesthetic neurotoxicity.The significance of developmental anesthetic neurotoxicity for human pediatric anesthesia is not emerging because of limitations with clinical settings.Trend The Food and Drug Administration advisory committee meeting conclude that no change in clinical practice is justified based on available data.More research is needed to deepen knowledge of developmental anesthetic neurotoxicity. Key words: General anesthetics; Developing brain; Neuroapoptosis; Synaptic plasticiy; Cognitive dysfunction

Neurotoxicity of General Anesthetics: An Update

Though general anesthetics have now been used clinically for well over a century, both their mechanisms of action as well as the nature of any potentially neurotoxic side effects remain elusive. With roughly 234 million people undergoing surgery each year worldwide, it remains imperative that any potentially deleterious effects of anesthetics be investigated and addressed. The issue of anesthetic- induced neurotoxicity in certain subsets of patients has continued to garner attention over the past decade, as more pre-clinical and clinical studies released are suggesting that inhalational and intravenous anesthetics may both cause and mitigate existing significant neuropathology. Pre-clinically, both cell-culture and animal studies suggest that anesthetics may cause neuroapoptosis, caspase activation, neurodegeneration, β-amyloid protein (Aβ) accumulation and oligomerization, and ultimately, deficits in neurocognition. Interestingly, however, newer data suggest that certain volatile anesthetics, such as desflurane, may have a less harmful neurotoxic profile compared to others in the pre-clinical and clinical settings. Continued pre-clinical investigation may have significant impact on clinical practice in the near future. Clinically, recent studies have raised awareness that exposure to general anesthetics during childhood may be associated with an increased risk for subsequent deficits in learning, memory, and cognition. Furthermore, retrospective studies continue to allude to the potential effects of surgery and anesthesia on cognitive trajectory, and more specifically, post-operative cognitive dysfunction (POCD) in the elderly. Studies to date regarding both of these clinical topics, however, are fraught with confounders, and many are underpowered statistically. The aim of this review is to examine the current data (both pre-clinical and clinical) on anesthetic-induced neurotoxicity and argue that further data are needed to either support or refute the potential connection between anesthetics and neurotoxicity.

Neurotoxicity of General Anesthetics

General anesthetics are highly lipid soluble and can dissolve in every membrane, penetrate into organelles and interact with numerous cellular constituents. Their actions have long been considered rapid and fully reversible, with the pharmacodynamic time course of anesthesia dictated solely by the pharmacokinetic profiles of anesthetic uptake and elimination. But recent laboratory data call for a cautious reassessment of this assumption. In the last decade, it has become apparent that anesthetics can affect gene expression, protein synthesis and processing, and cellular function in poorly understood ways that provide plausible biochemical substrates for durable long-term effects in a number of tissues. While in most patients physiological homeostasis is restored soon following general anesthesia, anesthetics have potentially profound and long-lasting effects that, in animal models, appear particularly consequential in specific developmental periods and pathophysiological contexts. Could a class of drugs employed for many decades without evidence of long-term damage have insidious and heretofore unrecognized neurotoxic effects? Here we critically evaluate available scientific evidence for general anesthetic ‘neurotoxicity’ and the potential clinical implications. Since the scope of this clinical commentary is limited, numerous deserving laboratory investigations could not be mentioned in this focused overview. Our goal as physician-scientists not directly involved in this area of research is to summarize the diverse directions of research in this field, while highlighting the limitations of existing data with respect to clinical practice in order to provide the reader with a rational platform for discussions with colleagues and patients. The barriers that must be overcome to permit clinical translation of the available laboratory research are emphasized, along with the need for further research, as recently highlighted in a consensus statement by a group including authoritative researchers in this field.1 As with any emerging field of research, new evidence continues to accrue such that conclusions are by necessity preliminary and will require frequent reappraisal.

Neurotoxicity of general anesthetics on developing brain

全身麻醉是否影响患儿智力发育在儿科麻醉学尚无定论.动物模型提示全麻药在未成熟哺乳动物大脑的快速生长期可激发大脑神经元的大量凋亡,这引起了麻醉学家对麻醉在人类新生儿和婴儿中应用安全性的强烈讨论。

Advance in neurotoxicity of general anesthetics to brain development

Transient blockade of glutamate N-methyl-D-aspartate (NMDA) receptors or excessive activation of GABAA receptors may trigger neuronal apoptosis in immature mammalian brain during the period of rapid brain growth. It has been shown that anesthetics, anticonvulsants, and drugs of abuse may induce apoptotie neurodegeneration via same mechanism and may affect the development of human brain. Key words: NMDA receptors; GABAA receptors; general anesthetics; apoptosis; brain development